Micheala A. Aldred Ph.D.

Associate Staff

Our work focuses on the genetics of pulmonary arterial hypertension (PAH), a serious lung vascular disorder. A subset of PAH cases are caused by germline mutations in genes of the bone morphogenetic protein (BMP) pathway, primarily BMPR2, but also SMAD9, ALK1 and endoglin. However, most cases are sporadic and the cause it unknown. Our hypothesis is that somatic genetic changes, which are not inherited and occur only in the lung, contribute to the pathogenesis of PAH. In collaboration with researchers at the Cleveland Clinic and elsewhere in the US, we have identified frequent chromosomal abnormalities in endothelial cells isolated from the lungs of patients with PAH. We are now characterizing the functional changes associated with these abnormalities. We are also profiling additional genetic and epigenetic changes that may occur in PAH lungs. A second project is to understand the role of microRNAs, small RNA molecules that regulate gene networks. A subset of microRNAs are regulated by the BMP pathway and we have shown that mutations in patients with familial PAH lead to loss of the pathway. We are also studying the role of circulating endothelial progenitor cells (EPCs). In work funded by the American Heart Association, we are examining whether the characteristics of EPCs correlate with gene mutation status and also how their gene expression profiles differ from EPCs from control subjects. The long-term goal of these studies is to identify early markers of PAH and pathways that might be targeted by new treatments.

In other words ...

Pulmonary arterial hypertension (PAH), is a life-threatening condition affecting the lungs and heart. Changes in the blood vessels of the lung lead to narrowing of the lumen, the space where blood flows, meaning that the pressure needed to pump blood through the lungs increases. This increased pressure in turn puts strain on the right ventricle of the heart. Our research examines the genetic changes that contribute to PAH. A small proportion of PAH cases are due to inherited genetic changes, but most are sporadic and have no known cause. We are studying the effects of these inherited genetic changes in families with PAH. In the sporadic cases, we are using new approaches to test whether there are genetic alterations occurring just in the lung, which might contribute to development of PAH. Our long-term goal is to identify new treatments that directly target these genetics changes and could potentially prevent the onset of disease in people who are at high risk of developing PAH.